The proposed research is designed to increase our understanding of human X-chromosome inactivation. Specifically we plan to investigate whether X-inactivation is modified in structurally abnormal X chromosomes so that loci such as steroid sulfatase (STS) which escape X-inactivation on structurally normal human inactive X's, undergo inactivation when present on a structurally abnormal inactive X. Mouse-human hybrids containing structurally abnormal inactive human X chromosomes will be isolated and evaluated for the expression of human STS. Secondly, we wish to investigate whether the inactive X in huma cells derived from trophectoderm is maintained in the inactive state by a DNA modification mechanism, as appears to be the case in somatic cells. In order to test this, transformation studies will be performed using DNA isolated from human chorionic villi obtained from abortus material. Thirdly, we wish to map the chromosomal location of the STS locus in mouse using somatic cell hybrids segregating mouse chromosomes. The long-term goal of this research is to elucidate the mechanism of X-chromosome inactivation. Since sex-linked diseases and X chromosome aneuploid states make up a substantial portion of the human genetic disease burden, the results of these studies will have practical importance. In addition, these investigations should provide useful information regarding control of gene expression with attendant implications for developmental biology, and neoplastic cell growth.